The primary objective of the proposed research is to better delineate the nature of the molecular events which cause the early decline of the rate of protein synthesis in skeletal muscle after hind limbs of rats are imm bilized with plaster casts. Answers to the following related questions are sought: (1) do increased glucocorticoid levels play a role in inhibiting protein synthesis; (2) does the development of insulin resistance by the muscle cause a decline in protein synthesis activity; (3) is the decline in protein synthesis related to a decreased ability of the cell-free ribosomal preparation to synthesize polypeptide chains; and (4) do calcium po l levels change in such a manner as to contribute to a decline in protein synthesis. The second major objective is to determine whether insulin resistance plays a role in the atrophy of skeletal muscles. Muscular atrophy and insulin resistance occur in diabetes and obesity, as in other diseases such as cancer, cystic fibrosis, acromegaly, Cushing's syndrome, myotonic dystrophy, etc. Using normal animals as a control, we propose to determine whether protein synthesis activity is less for a given dosage of insulin during the in vitro incubation of skletal muscles from diabetic-obese animals. We propose then to relate these findings to the glucose uptake per insulin concenration and to the insulin binding characteristics in skeletal muscles. Since physical exercise is known to improve glucose tolerance and to decrease insulin requirements in diabetic humans, we inend to exercise diabetic-obese animals and to subsequently compile data in order to determine whether glucose uptake by skeletal muscle increases per dosage of insulin, and whether the affinity of insulin receptors in muscle increases after a single bout of exercise.